Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades

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en

Abstract:

NOD-like receptor 3 (NLRP3) plays critical roles in the initiation of inflammasome-mediated inflammation in
microglia, thus becomes an important therapeutic target of Alzheimer’s disease (AD). Dexmedetomidine (Dex), a
new type of clinical anesthetic agent, shows anti-inflammatory properties and inhibits postoperative cognitive
dysfunction in AD patients. The present study was aimed to investigate effect of Dex on NLRP3 activity in activated
microglia and reveal the underlying mechanisms. The human microglia clone 3 (HMC3) cells were exposed
to 100 ng/ml LPS and 5 mM ATP, in the presence and absence of doses of Dex. Data from ELISA and Western
blot assays showed that Dex abrogated the promoting effects of LPS/ATP on the release of pro-inflammatory
cytokines including IL-1ß and IL-18 in the cell medium and the expression of NLRP3 and its downstream target
caspase-1 in HMC3 cells. Furthermore, the present study found that exposure of HMC3 cells to LPS/ATP increased
nuclear protein levels of transcription factor c-Fos, but treatment with Dex reversed the increase in c-Fos,
as indicated by Western blot and immunofluorescence measures. Luciferase reported assay revealed that c-Fos can
bind to the promoter region of NLRP3 gene and positively regulate the expression. These results suggest that Dex
inhibiting c-Fos nuclear protein levels promoted by LPS/ATP blocks the up-regulation of NLRP3. This suggestion
is supported by co-immunoprecipitation and PCR studies, in which Dex decreased the amount of c-Fos that binds
to NLRP3 under the stimulation of LPS/ATP. The present study revealed that Dex inhibits inflammation in microglia
cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades, which adds new understanding
of the anti-inflammatory mechanism of Dex.